Table 1. Baseline characteristics, patients with and without invasive Group A streptococcus.
Values are median (Q1–Q3) or number (%)
|
Non-iGAS
n = 968
|
iGAS
n = 53
|
p-valuea
|
Age (years)
|
68 (59–76)
|
63 (50–70)
|
0.008*
|
Female
|
421 (44)
|
20 (38)
|
0.48
|
SAPS 3b score
|
71 (61–81)
|
62 (56–72)
|
< 0.001*
|
SAPS 3 EMRc (%)
|
40 (21–61)
|
22 (14–42)
|
< 0.001*
|
Septic shock (Sepsis 3)d
|
486 (50)
|
32 (60)
|
0.16
|
Comorbidities:
|
|
|
|
Malignancye
|
154 (16)
|
3 (5.7)
|
0.049 *
|
Blood malignancyf
|
91 (9.4)
|
1 (1.9)
|
0.08
|
Cirrhosisg
|
30 (3.1)
|
3 (5.7)
|
0.24
|
Heart failureh
|
82 (8.5)
|
2 (3.8)
|
0.31
|
Immunosuppressioni
|
105 (11)
|
2 (3.8)
|
0.11
|
Origin of admission:
|
|
|
|
General ward
|
527 (54)
|
21 (40)
|
0.047*
|
Emergency department
|
230 (24)
|
18 (34)
|
0.10
|
Operating room
|
77 (8)
|
8 (15)
|
0.074
|
Other ICUj
|
106 (11)
|
5 (9.4)
|
1.00
|
Postoperative care unit
|
26 (2.7)
|
1 (1.9)
|
1.00
|
Reason for admissionk:
|
|
|
|
Cardiovascularl
|
145 (15)
|
38 (72)
|
< 0.001*
|
Hepatic
|
56 (5.8)
|
1 (1.9)
|
0.36
|
Abdominalm
|
176 (18)
|
9 (17)
|
1.00
|
CNSn
|
164 (17)
|
12 (23)
|
0.27
|
Renal
|
320 (33)
|
21 (40)
|
0.37
|
Pulmonary
|
206 (21)
|
17 (32)
|
0.09
|
Metabolic
|
189 (20)
|
9 (17)
|
0.72
|
Not coded
|
124 (13)
|
4 (7.5)
|
0.39
|
Physiological and laboratory variables at admissiono:
|
|
|
|
Heart rate
|
107 (93–122)
|
108 (94–125)
|
0.85
|
SBPp (mmHg)
|
103 (86–126)
|
104 (86–121)
|
0.94
|
Lactate (mmol/L)
|
2.6 (1.5–4.5)
|
2.5 (1.8–4.9)
|
0.55
|
Norepinephrine (μg/min/first 6 h)
|
2.3 (0–7.7)
|
2.6 (0–12)
|
0.10
|
Temperature (°Celsius)
|
37.2 (36.5–38.0)
|
37.5 (36.9–38.0)
|
0.10
|
Leucocytes (×109/L)
|
11 (5.2–19)
|
10.5 (5.1–18)
|
0.78
|
Platelets (×109/L)
|
160 (92–265)
|
163 (107–208)
|
0.42
|
pH
|
7.36 (7.27–7.43)
|
7.36 (7.29–7.42)
|
0.92
|
Bilirubin (μmol/L)
|
15 (9.0–26)
|
14 (8.0–21)
|
0.49
|
Creatinine (μmol/L)
|
133 (86–208)
|
173 (100–311)
|
0.02*
|
APTTq (s)
|
40 (33–51)
|
38 (34–44)
|
0.19
|
PK-INRr
|
1.4 (1.2–1.7)
|
1.3 (1.2–1.4)
|
0.004*
|
a Fisher’s exact test or Mann Whitney, * = p ≤ 0.05
b Simplified acute physiologic score 3
c Estimated mortality rate
d All patients included in the study were diagnosed with severe sepsis or septic shock according to Sepsis 2 definition. Patients in both groups were also described as having septic shock (Sepsis 3) or not.
e Cancer spread beyond the regional lymph nodes
f Lymphoma, acute leukemia or myeloma
g Biopsy confirmed or clinical signs of portal hypertension
h NYHA class IV (fatigue, dyspnea, angina at rest)
i Chronic steroid treatment correlative to ≥ 0.3 mg/kg prednisolone/day, radiation, or chemo therapy
j Intensive care unit
k Patients may have multiple reasons for admission
l Hypovolemia, cardiac shock, mixed shock, anaphylactic shock, arrhythmia or cardiac arrest
m Gastro-intestinal bleeding, acute abdomen or pancreatitis
n Convulsions, decreased consciousness, coma, delirium or intracranial volume effect
o Blood samples taken within 90 minutes after admission
p Systolic blood pressure
q Activated partial thromboplastin time
r Prothrombin time - international normalised ratio
Table 2a. Culture results, in the control group.
Culture result
|
Frequency, n (%)
|
Negative culture
|
340 (45)
|
Escherichia coli
|
98 (13)
|
Staphylococcus aureus
|
46 (6.1)
|
Streptococcus pneumoniae
|
40 (5.3)
|
Beta-hemolytic streptococci non-GAS
|
10 (1.3)
|
Candida species
|
20 (2.7)
|
Neisseria meningitides
|
2 (0.3)
|
Enterococcus species
|
32 (4.3)
|
Pseudomonas aeruginosa
|
16 (2.1)
|
Other gram-positive bacteriaa
|
126 (17)
|
Other gram-negative bacteriab
|
71 (9.5)
|
Mixed florac
|
3 (0.4)
|
Fusarium solani
|
1 (0.1)
|
Cultures from blood or other sterile sites from 749 of the patients in the control group. 95 patients had positive cultures with microorganisms from more than one of the aggregated groups or the GAS-group.
a Streptococcus species (Alpha, anginosus, bovis, intermedius, lutetiensis, mitis and salivarius), Coagulase-negative Staphylococcus (S.epidermis, haemolyticus, hominis and sciuri), Eggerthella lenta, Parvimonas micra, Bacteroides species, Propionibacterium, Anaerobic gram-positive rods, Clostridium species (cadaveris, innocuum, paraputrificum, septicum, ramosum, bifermentans and perfringens), Peptostreptococcus stomatis, Cutibacterium (Propionibacterium) acnes, Parabacteroides distasonis, Enterococcus gallinarum, Gemella species, Flavonifractor plautii, Globicatella species, Granulicatella species, Lactobacillus species, Anaerococcus species, Actinomyces odontolyticus, Corynebacterium species, Gemella morbillorum, Paenibacillus species and Peptoniphilus harei.
b Proteus mirabilis, Klebsiella (aerogenes, oxytoca and pneumonia), gram-negative rods, Prevotella denticola, Serratia marcescens, Enterobacter cloacae, Dialister pneumosintes, Citrobacter (freundii and diversus), Morganella morganii, Salmonella enterica serogroup Rissen, Prevotella species, Proteus vulgaris, Stenotrophomonas maltophilia, Neisseria species, Haemophilus (influenza and parainfluenzae), Sphingomonas species, Providencia rettgeri, Prevotella buccae and Fusobacterium necrophorum.
c Anaerob mixed flora, skin flora, mixed flora
Table 2b. Infection sites, control group, n = 968
|
Pneumonia
|
340 (35)
|
Abdominal or urinary tract
|
259 (27)
|
Central nervous system
|
25 (2.6)
|
Soft tissue
|
19 (2.0)
|
Gynecological
|
18 (1.9)
|
Other[i]
|
307 (32)
|
i Including but not limited to catheter related infection, prosthesis infection and sepsis without known focus.
Table 3. Patient characteristics and outcomes in iGAS patients without or with emm1/T1.
Values are median (Q1-Q3) or number (%)
|
iGAS without emm1/T1 n = 25
|
iGAS with emm1/T1, n = 25
|
p-valuea
|
Origin of infection:
|
|
|
|
Soft tissue
|
11(44)
|
18 (72)
|
0.08
|
Necrotizing fasciitis
|
7 (28)
|
12 (48)
|
0.24
|
Pneumonia
|
3 (12)
|
3 (12)
|
1.00
|
Puerperal
|
2 (8.0)
|
0
|
0.49
|
Arthritis
|
4 (16)
|
0
|
0.11
|
Pharyngeal/parapharyngeal
|
1 (4.0)
|
2 (8.0)
|
1.00
|
Mastoiditis
|
1 (4.0)
|
0
|
1.00
|
Meningitis
|
0
|
1 (4.0)
|
1.00
|
Un-known focus
|
3 (12)
|
1 (4.0)
|
0.61
|
Septic shock (Sepsis 3)b
|
11 (44)
|
10 (40)
|
1.00
|
IVIGc
|
7 (28)
|
13 (52)
|
0.15
|
DAFd vasopressor
|
26 (25-28)
|
25 (23-26)
|
0.036*
|
DAFd ventilation
|
26 (20-28)
|
24 (20-26)
|
0.23
|
CRRTe
|
4 (16)
|
8 (32)
|
0.32
|
AKIN-creaf
|
0 (0-3)
|
3 (0-3)
|
0.007*
|
SOFA maxg
|
9 (6-13)
|
12 (7-14)
|
0.11
|
Length of stay; survivors
|
2.7 (1.2-4.7)
|
5.1 (2.3-7.5)
|
0.08
|
SAPS 3h
|
65 (54-70)
|
61 (58-78)
|
0.27
|
EMRi
|
28 (11-39)
|
21 (15-54)
|
0.27
|
ICUj mortality
|
2 (8.0)
|
1 (4.0)
|
1.00
|
28-day mortality
|
5 (20)
|
1 (4.0)
|
0.19
|
90-day mortality
|
6 (24)
|
2 (8.0)
|
0.25
|
180-day mortality
|
8 (32)
|
3 (12)
|
0.17
|
a Fisher’s exact test or Mann Whitney, * = p ≤ 0.05
b All patients included in the study were diagnosed with severe sepsis or septic shock according to Sepsis 2 definition. Patients in the iGAS group were also described as having septic shock (Sepsis 3) or not.
c Intravenous immunoglobulin
d Days alive and free
e Continuous renal replacement therapy
f Maximum acute kidney injury network classification score the first 10 days after admission
g Maximum sequential organ failure assessment score during ICU admission
h Simplified acute physiology score 3
i Estimated mortality rate
j Intensive care unit
Table 4. Outcomes with univariate testing comparing non-iGAS patients with iGAS patients
Values are median (Q1-Q3) or number (%)
|
Non-iGAS
n = 968
|
iGAS
n = 53
|
p-valuea
|
DAFb vasopressor
|
24 (25-26)
|
25 (22-26)
|
0.04*
|
Vasopressor free daysc
|
24 (0-26)
|
25 (23-26)
|
0.027*
|
DAFb ventilator
|
23 (3-28)
|
25 (20-28)
|
0.02*
|
Ventilator free daysc
|
23 (0-28)
|
25 (19-28)
|
0.046*
|
CRRTd
|
185 (19)
|
12 (23)
|
0.48
|
AKIN-creae
|
0 (0-3)
|
3 (0-3)
|
0.045*
|
SOFA maxf
|
11 (8-14)
|
10 (6-14)
|
0.16
|
Length of stay; survivors
|
3.3 (1.5-6.8)
|
3.8 (1.8-7.0)
|
0.77
|
ICU mortality
|
237 (25)
|
3 (5.7)
|
<0.001*
|
28-day mortality
|
354 (37)
|
7 (13)
|
<0.001*
|
90-day mortality
|
429 (44)
|
9 (17)
|
<0.001*
|
180-day mortality
|
471 (49)
|
12 (23)
|
<0.001*
|
a Mann-Whitney or Fisher´s exact test (two-tailed)
b Days Alive and Free without extra penalty for death
c With extra penalty for death
d Continuous Renal Replacement Therapy
e Maximal Acute Kidney Injury Network classification score the first 10 days after admission
f Maximal Sequential Organ Failure Assessment, score during ICU-admission
Table 5. Associations between independent variables and outcomes.
All outcomes were analysed in separate multivariable regression models as described in the Methods section. Morbidity outcomes were reported for the first 28 days after admission. * = p ≤ 0.05.
Outcome
|
Age
|
SAPS 3a
|
iGAS
|
Severe sepsis or septic shock, n=1021
|
|
|
|
Mortality, CIb of HRc
|
1.002–1.016*
|
1.032-1.044*
|
0.204-0.746*
|
DAFd vasopressor, CIb of ORe
|
0.994–1.015
|
1.044-1.07*
|
0.897-3.681
|
DAFd ventilator CIb of ORe
|
0.977–0.997*
|
1.046-1.070*
|
0.694–2.330
|
CRRTf, CIb of ORe
|
0.979–1.002
|
1.031-1.054*
|
0.862-3.416
|
AKIN-creag, CIb of ORe
|
0.985–1.003
|
1.030-1.050*
|
1.246–4.968*
|
a Simplified acute physiology score 3
b Confidence interval (95%)
c Hazard ratio
d Days alive and free
e Odds ratio
f Continuous renal replacement therapy
g Acute kidney injury network (AKIN)-creatinine class 1 or worse